Several processes for the preparation of the 2-hydroxy-4-substituted pyridine compounds by chemical synthesis are reported. For example, as a process for the preparation of a 2-hydroxyisonicotinic acid or a precursor thereof, that is, 2-halogenoisonicotinic acid, a process whereby    [i] isonicotinic acid is reacted with fluorine gas at ice-bath temperature, and thereafter the reactant is hydrolyzed with hydrochloric acid to obtain a 2-hydroxyisonicotinic acid (U.S. Pat. No. 4,968,803: Patent Reference 1), or    [ii] isonicotinic acid N-oxide is reacted with phosphorus oxychloride and phosphorus pentachroride under refluxing to obtain a 2-chloroisonicotinic acid (Japanese Examined Patent Publication (Kokoku) 6-37472: Patent Reference 2), is known.
As a process for the preparation of a 2-hydroxy-4-cyanopyridine, a process whereby    [iii] 4-cyanopyridine N-oxide is reacted with trifluoroacetic anhydride for 7 days at 110° C. to obtain a 4-cyano-2-pyridone [Nucleosides & Nucleotides, 3(4), 369-388, (1984): Non-Patent Reference 1] is reported.
As a process for the preparation of 2-hydroxy-4-methylpyridine, a process whereby [iv] 4-methylpyridine is reacted with acetyl hypofluorite at −10° C. to obtain a 2-acetoxy-4-methylpyridine, and thereafter the 2-acetoxy-4-methylpyridine is hydrolyzed to obtain 4-methyl-2-pyridone is reported [Journal of the American Chemical Society, 109, 3789-3790, (1987): Non-Patent Reference 2].
A process for the preparation of a 2-hydroxyisonicotinamide is not known. In addition, 2-hydroxy-4-pyridinaldoxime, which is not described in any reference, is a novel compound.
However, among these preparing processes [i] to [iv], in the process [i] a careful handling of halogen gas is required, and further, a special apparatus is required in the reaction. In addition, the processes [ii] to [iv] are not considered as an industrial process, due to a use of particular reagents, a strict temperature conditions, and many complicated steps. Accordingly, these processes by chemical synthesis are not practical processes because the processes have many steps and materials requiring careful handling are used.
A process for the preparation of a 2-hydroxy-4 substituted pyridine by using a microbiological method has not been reported until now. As a microorganism which has an enzymatic activity capable of converting an isonicotinic acid into a 2-hydroxyisonicotinic acid, Sarcina species [Indian Journal of Biochemistry & Biophysics, 15, Dec., 492-493, (1978): Non-Patent Reference 3] and Mycobacterium species [Journal of General Microbiology, 137, 1073-1080, (1991): Non-Patent Reference 4] are known. However, the Non-Patent Reference 3 and Non-Patent Reference 4 are disclosed only an analysis of a metabolic pathway of the microorganisms and do not disclose the process of preparing the 2-hydroxyisonicotinic acid, which is a metabolic intermediate. Therefore, taking a capacity of enzyme production of the microorganisms and an amount of the 2-hydroxyisonicotinic acid accumulated into consideration, the process using the microorganisms can not be satisfactorily used in an industrial production of the 2-hydroxyisonicotinic acid.    [Patent Reference 1] U.S. Pat. No. 4,968,803    [Patent Reference 2] Japanese Examined Patent Publication (Kokoku) 6-37472    [Non-Patent Reference 1] Nucleosides & Nucleotides, 3(4), 369-388, (1984)    [Non-Patent Reference 2] Journal of the American Chemical Society, 109, 3789-3790, (1987)    [Non-Patent Reference 3] Indian Journal of Biochemistry & Biophysics, 15, Dec., 492-493, (1978)    [Non-Patent Reference 4] Journal of General Microbiology, 137, 1073-1080, (1991)